Ki calculation from the Binding Energy of poses generated by Autodock 4.2; source:
http://autodock.scripps.edu/faqs-help/faq/how-autodock-4-converts-binding-energy-kcal-mol-into-ki.
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equilibrium:
binding:
dissociation:
E
E
+ I
+ I
EI
<=>
->
->
EI
EI
E +
I
K(binding),
Kb
K(dissociation), Kd
1
K(binding) = --------------K(dissociation)
so:
ln K(binding) = -ln K(dissociation)
ln Kb = -ln Kd
Ki = dissociation constant of the enzyme-inhibitor complex = Kd
[E][I]
Ki = -----[EI]
so:
ln Kb = -ln Ki
deltaG(binding)
= -R*T*ln Kb
deltaG(inhibition) = R*T*ln Ki
Binding and Inhibition occur in opposite directions, so we
lose the minus-sign: deltaG = R*T*lnKi, _not_ -R*T*lnKi
=> deltaG/(R*T) = lnKi
=> Ki = exp(deltaG/(R*T))
Figure S1. Energy plots of systems. Potential energy (Epot) and total energy (Etot), of hD2L and hD3
receptors.
Table S1. C deviations of transmembrane helices (TM) of D3 and D2L simulated receptors
from the starting models. C deviation values were determined by structural alignment of each
helix of the model and of the optimized structure.
TM helices D3-R
C deviation (Å)
I
0.486
II
0.523
III
0.501
IV
0.491
V
0.672
VI
0.740
VII
0.685
D2L-R
C deviation (Å)
0.688 *
0.903 *
0.722 *
0.841 *
1.213 */**
0.855 */**
0.877 */**
* Major transversal deviation in the intracellular side.
** Major transversal deviation in the extracellular side.
*/** Major transversal deviation in the intracellular and extracellular side.
Figure S2. Deviation of helices of optimized hD2L receptor (cyan cartoon) respect the starting
model (yellow cartoon). The upper side of the figure corresponds to the extracellular side.
Table S2. Computed pKi for ligands docked into hD3 and hD2L receptors. Values are reported
for ligands inserted in the regressions represented in Figure 7.
D3 agonist
Dopamine
r-7-OH-DPAT
r-7-OH-PIPAT
Pramipexole
Ropinirole
Rotigotine
PD 128907
cis-8-OH-PBZI
hD3
pKi
4.73
5.63
6.13
5.23
5.11
6.12
5.64
5.2
hD2
pKi
4.42
4.71
5.32
4.8
4.72
5.44
4.4
ND
Virtual screening results: the 30 top scored compounds (ZINC-db code) docked into hD3 and
hD2L. The lables _1 and _2 corresponds to different protonation states of ligands.
hD3: ZINC45254546, ZINC11847498, ZINC11847496, ZINC04138713, ZINC04262922,
ZINC11847499, ZINC04138711, ZINC11847497, ZINC04262921, ZINC04138712,
ZINC65739972_1, ZINC04138714, ZINC65739975_1, ZINC65739975, ZINC65739976_1,
ZINC63772249, ZINC29554524, ZINC29554520_1, ZINC65739972, ZINC65739978,
ZINC63772250, ZINC65739976, ZINC29554520, ZINC29554520_2, ZINC27555141,
ZINC27555141_1, ZINC00553652_1.
hD2L: ZINC04138714, ZINC04138712, ZINC45254546, ZINC63772250, ZINC11847497,
ZINC04262921, ZINC11847496, ZINC04138711, ZINC04262922, ZINC11847498,
ZINC63772249, ZINC29554524, ZINC65739978, ZINC65739978_1, ZINC65739976_1,
ZINC29554524_1, ZINC29554520, ZINC11847499, ZINC29554524_2, ZINC04138713,
ZINC29554520_2, ZINC29554520_1, ZINC00574128, ZINC65739976, ZINC65739975,
ZINC65739975_1, ZINC65739972.
Figure S3. Superimposition of template (3PBL)-homology model- optimized model of hD3
receptor and hD2L receptor. The template structure (green cartoon) is the A chain of hD3 receptor
crystal structure (3BPL). The cyan cartoon corresponds to the homology model of hD3 receptor, the
yellow cartoon corresponds to the homology model of hD2L receptor. The optimized models of hD3
and hD2L receptor are respectively the magenta and orange cartoons.